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    ABSTRACT: Epstein Barr virus (EBV) is a highly prevalent human gamma 1 lymphocryptovirus which infects both B lymphocytes and epithelial cells. In the healthy host, infection of these different cell lineages broadly reflects the different phases of the virus lifecycle. Memory B cells are the reservoir for latent EBV, in which viral gene expression is highly restricted to maintain an asymptomatic lifelong infection. In contrast, epithelial cells may be a major site of the virus lytic cycle, where infectious virus is propagated and transmitted via saliva to uninfected hosts. To achieve this dual tropism, EBV has evolved a unique set of glycoproteins in addition to a highly conserved set, which interact with cell lineage-specific receptors and switch cellular tropism during infection.
    Current opinion in virology. 02/2014; 4C:78-84.
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    ABSTRACT: Background Malignant brain tumors in children generally have a very poor prognosis when they relapse and improvements are required in their management. It can be difficult to accurately diagnose abnormalities detected during tumor surveillance, and new techniques are required to aid this process. This study investigates how metabolite profiles measured noninvasively by (1)H magnetic resonance spectroscopy (MRS) at relapse reflect those at diagnosis and may be used in this monitoring process.Methods Single-voxel MRS (1.5 T, point-resolved spectroscopy, echo time 30 ms, repetition time 1500 ms was performed on 19 children with grades II-IV brain tumors during routine MRI scans prior to treatment for a suspected brain tumor and at suspected first relapse. MRS was analyzed using TARQUIN software to provide metabolite concentrations. Paired Student's t-tests were performed between metabolite profiles at diagnosis and at first relapse.ResultsThere was no significant difference (P > .05) in the level of any metabolite, lipid, or macromolecule from tumors prior to treatment and at first relapse. This was true for the whole group (n = 19), those with a local relapse (n = 12), and those with a distant relapse (n = 7). Lipids at 1.3 ppm were close to significance when comparing the level at diagnosis with that at distant first relapse (P = .07, 6.5 vs 12.9). In 5 cases the MRS indicative of tumor preceded a formal diagnosis of relapse.Conclusions Tumor metabolite profiles, measured by MRS, do not change greatly from diagnosis to first relapse, and this can aid the confirmation of the presence of tumor.
    Neuro-Oncology 12/2013;
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    ABSTRACT: Background:Epithelial cell adhesion molecule is overexpressed in bladder tumours and released from bladder cancer cells in vitro. We test the hypotheses that urinary EpCAM could act as a biomarker for primary bladder cancer detection and risk stratification.Methods:Epithelial cell adhesion molecule was measured by ELISA in urine from 607 patients with primary bladder tumours and in urine from 53 non-cancer controls. Mann-Whitney tests and ROC analyses were used to determine statistical significance and discrimination between non-cancer controls and different stages and grades of disease. Multivariable modelling and Kaplan-Meier analyses were used to determine prognostic significance. The structure of urinary EpCAM was investigated by western blotting and mass spectrometry.Results:Urinary EpCAM levels increase with stage and grade of bladder cancer. Alongside grade and stage, elevated urinary EpCAM is an independent indicator of poor prognosis with a hazard ratio of 1.76 for bladder cancer-specific mortality. The soluble form of EpCAM in urine is the extracellular domain generated by cleavage between ala243 and gly244. Further studies are required to define the influence of other urinary tract malignancies and benign urological conditions on urinary EpCAM.Conclusion:The extracellular domain of EpCAM is shed into urine by bladder tumours. Urinary EpCAM is a strong indicator of bladder cancer-specific survival, and may be useful within a multi-marker panel for disease detection or as a stand-alone marker to prioritise the investigation and treatment of patients. The mechanisms and effects of EpCAM cleavage in bladder cancer are worthy of further investigation, and may identify novel therapeutic targets.British Journal of Cancer advance online publication, 28 November 2013; doi:10.1038/bjc.2013.744 www.bjcancer.com.
    British Journal of Cancer 11/2013;
  • Praxis 11/2013; 102(23):1427-9.
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    ABSTRACT: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer. 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing. FFPE cancer tissues, which had been stored for at least 4years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues. Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies.
    Experimental and Molecular Pathology 10/2013;
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    ABSTRACT: The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumour microenvironment which is composed of a variety of cell types, as well as non-cellular components such as collagen. Although HRS cells harbour oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumour microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal centre B cells, the presumed progenitors of HRS cells, up-regulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently over-express DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75, Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumour microenvironment in promoting the oncogenic effects of EBV.
    Blood 10/2013;
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    ABSTRACT: SUMO conjugation is known to occur in response to double-stranded DNA breaks in mammalian cells, but whether SUMO deconjugation has a role remains unclear. Here, we show that the SUMO/Sentrin/Smt3-specific peptidase, SENP7, interacts with the chromatin repressive KRAB-associated protein 1 (KAP1) through heterochromatin protein 1 alpha (HP1α). SENP7 promotes the removal of SUMO2/3 from KAP1 and regulates the interaction of the chromatin remodeler CHD3 with chromatin. Consequently, in the presence of CHD3, SENP7 is required for chromatin relaxation in response to DNA damage, for homologous recombination repair and for cellular resistance to DNA-damaging agents. Thus, deSUMOylation by SENP7 is required to promote a permissive chromatin environment for DNA repair.
    EMBO Reports 09/2013;
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    ABSTRACT: Intestinal stomas are common. Muslims report significantly lower quality of life following stoma surgery compared to non-Muslims. A fatwā is a ruling on a point of Islamic law according to a recognised religious authority. The use of fatawās to guide health-related decision-making has becoming an increasingly popular practice amongst Muslims, regardless of geographic location. This project aimed to improve the quality of life of Muslim ostomates by addressing faith-specific stoma concerns. Through close collaboration with Muslim ostomates, a series of 10 faith-related questions were generated, which were posed to invited local faith leaders during a stoma educational event. Faith leaders received education concerning the realities of stoma care before generating their fatawās. The event lead to the formulation of a series of stoma-specific fatawās representing Hanafi and Salafi scholarship, providing faith-based guidance for Muslim ostomates and their carers. Enhanced communication between healthcare providers and Islamic faith leaders allows for the delivery of informed fatawās that directly benefit Muslim patients and may represent an efficient method of improving health outcomes in this faith group.
    Journal of Religion and Health 09/2013;
  • Nature Immunology 08/2013; 14(9):886-7.
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a cancer common in Southern China and South East Asia that is causally linked to Epstein-Barr virus (EBV) infection. Here, we demonstrate that NPC displays frequent dysregulation of the Hedgehog (HH) pathway, a pathway implicated in the maintenance of stem cells, but whose aberrant activation in adult tissues can lead to cancer. Using authentic EBV-positive carcinoma-derived cell lines and nasopharyngeal epithelial cell lines latently infected with EBV as models for NPC in vitro, we show that EBV activates the HH signalling pathway through autocrine induction of SHH ligand. Moreover, we find that constitutive engagement of the HH pathway induces the expression of a number of stemness-associated genes and imposes stem-like characteristics on EBV-infected epithelial cells in vitro. Using epithelial cells expressing individual EBV latent genes detected in NPC, we show that EBNA1, LMP1 and LMP2A are all capable of inducing SHH ligand and activating the HH pathway, but only LMP1 and LMP2A are able to induce expression of stemness-associated marker genes. Our findings not only identify a role for dysregulated HH signalling in NPC oncogenesis but also provide a novel rationale for therapeutic intervention.
    The Journal of Pathology 08/2013;
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